1,2-Dichloroethane → 6-Bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide

HRID 1476961Notes

Reaction equation

HRID 1476961 reaction equation
[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14](=[O:20])OC(C)(C)C)[CH3:2].C(O)(C(F)(F)F)=O.[Br:28][C:29]1[CH:30]=[C:31](C(O)=O)[C:32]2[CH:33]=[CH:34][N:35]([CH:38]([CH3:40])[CH3:39])[C:36]=2[CH:37]=1.CN1CCOCC1.C(Cl)CCl>ClCCl>[Br:28][C:29]1[CH:30]=[C:31]([C:14]([NH:13][CH2:12][C:5]2[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=2[NH:3][CH2:1][CH3:2])=[O:20])[C:32]2[CH:33]=[CH:34][N:35]([CH:38]([CH3:40])[CH3:39])[C:36]=2[CH:37]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 6422Trifluoroacetic acidHCID 79724-MethylmorpholineHCID 674686386-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acidHCID 674691351,1-Dimethylethyl {[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}carbamate

Product 1

HCID 674685206-Bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In a 50 mL round bottom was added 1,1-dimethylethyl {[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}carbamate (500 mg, 1.777 mmol) and Dichloromethane (DCM) (20.00 mL). TFA (1.095 mL, 14.22 mmol) was added and the reaction stirred at rt for 3.5 h. The LCMS indicated deprotection. The reaction was evaporated and evaporated from DCM. Dimethyl Sulfoxide (DMSO) (20 mL) was added to the round bottom followed by 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acid (501 mg, 1.777 mmol), to the solution was added N-methylmorpholine (1.172 mL, 10.66 mmol) 1-hydroxy-7-azabenzotriazole (363 mg, 2.67 mmol) and EDC (511 mg, 2.67 mmol). The reaction stirred at rt for 12 hr. The reaction was poured onto Ice water (10 mL) and was stirred for 20 min let it rest for 10 min and filter. Rinse solid with water (10 mL). Purification of solid by reverse phase Gilson HPLC (10-90% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes) provided the desired product as a white solid after neutralization with 0.1N NaOH and evaporation and precipitation from water. 6-bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide (240 mg, 0.523 mmol, 29.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.70 (s, 1H) 8.87 (m, 1H) 7.93 (s, 1H) 7.57-7.71 (m, 2H) 6.89 (d, J=3.28 Hz, 1H) 6.71 (m, 1H) 5.66 (s, 1H) 4.82 (m, 1H) 4.34 (d, J=5.81 Hz, 2H) 3.12-3.23 (m, 2H) 2.08 (s, 3H) 1.43 (d, J=6.57 Hz, 6H) 1.18 (t, 3H) MS(ES) [M+H]+ 445.1.

Workup

  1. customThe reaction was evaporated
  2. customevaporated from DCM
  3. additionDimethyl Sulfoxide (DMSO) (20 mL) was added to the round
  4. stirringThe reaction stirred at rt for 12 hr
  5. additionThe reaction was poured onto Ice water (10 mL)
  6. stirringwas stirred for 20 min
  7. waitrest for 10 min
  8. filtrationfilter
  9. washRinse solid with water (10 mL)
  10. customPurification of solid by reverse phase Gilson HPLC (10-90% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes)

Sources & evidence

ORD record
ord-dcca0e36c6b5457bbbf682a57515c3c9
Source dataset
uspto-grants-2016_08
Patent number
US09402836B2

Reaction notes

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